Use of pyrimidine—or triazine—2 carbonitiles for treating diseases associated with cysteine prostease activity and novel pyrimidine-2-carbonitile derivatives

ABSTRACT

The present invention therefore provides use of a compound of formula (I) and compositions for treating diseases associated with cysteine protease activity. The compounds are reversible inhibitors of cysteine proteases S, K, F, L and B. Of particular interest are diseases associated with Cathepsin S. In addition, this invention also discloses processes for the preparation of such inhibitors

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a US National Stage under 35 U.S.C § 371 ofInternational Application No. PCT/SE2003/001078 that was filed on Jun.23, 2003. The International Application claims priority under 35 U.S.C §119(a)–(d) to Swedish Application No. 0201976-8 filed Jun. 24, 2002.

The present invention relates to compounds and compositions for treatingdiseases associated with cysteine protease activity. The compounds arereversible inhibitors of cysteine proteases S, K, F, L and B. Ofparticular interest are diseases associated with Cathepsin S. Inaddition this invention also discloses processes for the preparation ofsuch inhibitors.

BACKGROUND OF THE INVENTION

Cathepsin S is a member of the papain superfamily of cysteine proteaseswhich also encompasses Cathepsins B, H, L, O and K. Cathepsin S plays akey role in the processing of invariant chain in MHC class II complexesallowing the complex to associate with antigenic peptides. MHC class IIcomplexes are then transported to the surface of the cell forpresentation to effector cells such as T cells. The process of antigenpresentation is a fundamental step in initiation of the immune response.In this respect inhibitors of cathepsin S could be useful agents in thetreatment of inflammation and immune disorders such as, but not limitedto, asthma, rheumatoid arthritis, multiple sclerosis and Crohn'sdisease. Cathepsin S has also been implicated in a variety of otherdiseases involving extracellular proteolysis such as the development ofemphysema in COPD through degradation of elastin and in Alzheimersdisease.

Other Cathepsins notably K and L have been shown to degrade bonecollagen and other bone matrix proteins. Inhibitors of these cysteineproteases would be expected to be useful in the treatment of diseasesinvolving bone resorption such as osteoporosis.

The present invention therefore provides use of a compound of formula(I)

in which:

-   X is N or CA where A is hydrogen, halogen, CHR²R³, OR², NR²R³, SR²;-   R² and R³ are independently hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl    both of which can optionally contain one or more O, S or NR⁴ groups    where R⁴ is hydrogen or C₁₋₆ alkyl, and can be optionally    substituted by aryl, heteroaryl, NR⁵R⁶ where R⁵ and R⁶ together with    the nitrogen atom to which they are attached form a 4–7 membered    ring optionally containing a further O, S, NR⁴, or R2 and R3    together with the nitrogen atom to which they are attached form a    4–7 membered ring optionally containing a further O, S, NR⁴ group,    or R2 and R3 are aryl or heteroaryl groups, both aryl and heteroaryl    groups being optionally substituted by halogen, amino, hydroxy,    cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl,    NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆    alkoxy, NR⁷R⁸ or SR⁷ where R⁷ and R⁸ are independently hydrogen or    C₁₋₆ alkyl;-   R and R¹ are independently a group Y(CH₂)pR⁹ where p is 0, 1, 2 or 3    and Y is O or NR¹⁰ where R¹⁰ is hydrogen, C₁₋₆ alkyl or C₃₋₆    cycloalkyl;-   and R⁹ is hydrogen, C₁₋₆ alkyl which can optionally contain one or    more O, S or NR⁴ groups where R⁴ is hydrogen or C₁₋₆ alkyl, or a 3    to 7-membered saturated ring optionally containing a carbonyl group,    one or more O, S or N atoms, or an aryl or heteroaryl group    containing one to four heteroatoms selected from O, S or N, the    saturated ring, aryl and heteroaryl groups all being optionally    substituted by halogen, amino, hydroxy, cyano, nitro, carboxy,    CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴,    ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆ alkoxy, SR⁵ or    NR¹¹R¹² where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or    together with the nitrogen atom to which they are attached form a 5-    or 6-membered saturated ring optionally containing a further O, S or    NR⁴ group;-   or R/R¹ is a group NR¹⁰(CHR¹⁰)CONR²R³ or NR¹⁰(CH₂)_(q)CONR²R³ where    q is 1, 2 or 3;-   or R/R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴ together with the    nitrogen atom to which they are attached form a 4 to 7-membered    saturated ring optionally containing a carbonyl group, O, S or N    atom and optionally substituted by C₁₋₆ alkyl, amino, hydroxy,    CO₂C₁₋₆ alkyl, halogen, NR⁵R⁶, NR⁷R⁸, C₁₋₆ alkylNR¹⁷R¹⁸ where R¹⁷    and R¹⁸ are independently hydrogen or C₁₋₆ alkyl, CONR¹⁵R¹⁶ where    R¹⁵ and R¹⁶ are independently hydrogen or C₁₋₆alkyl, or optionally    substituted by aryl, phenoxy, COphenyl, or a heteroaryl group, the    latter four groups being optionally substituted by halogen, amino,    hydroxy, cyano, nitro, carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴,    trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy, methylenedioxy,    C₁₋₆ alkyl, C₁₋₆ alkoxy, SR⁵ or NR¹¹R¹² where R¹¹ and R¹² are    independently hydrogen, C₁₋₆ alkyl or together with the nitrogen    atom to which they are attached form a 5- or 6-membered saturated    ring optionally containing a further O, S or NR⁴ group;    and pharmaceutically acceptable salts or solvates thereof, in the    manufacture of a medicament for use in the inhibition of cathepsin S    in a mammal such as man.

In the context of the present specification, unless otherwise indicated,an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituentgroup may be linear or branched. Aryl groups include phenyl andnaphthyl. Heteroaryl groups include 5- or 6-membered, 5,6- or 6,6-fusedheterocyclic rings containing one or more heteroatoms selected from N,S, O. Examples include pyridine, pyrimidine, thiazole, oxazole,pyrazole, imidazole, furan, thiophene, quinoline, isoquinoline,benzimidazole, benzofuran, benzothiophene and indole.

Certain compounds of formula (I) are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses all geometric and optical isomers of the compounds offormula (I) and mixtures thereof including racemates. Tautomers andmixtures thereof also form an aspect of the present invention.

Preferably X is CH, NHR², OR² where R² is preferably H or C₁₋₆ alkyl.

Preferably R is a group Y(CH₂)_(p)R⁷ where p is 0 or 1 and Y is NR⁸where R⁸ is hydrogen and R⁷ is substituted phenyl. Preferably R⁷ isphenyl substituted by halogen, especially chloro. More preferably R⁷ isphenyl substituted by chloro in the 4-position.

Preferably R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴ together with thenitrogen atom to which they are attached form a morpholine ring,piperidine or piperazine ring optionally substituted, or R¹ is a groupNR⁹R¹⁰ where R¹⁰ is H or C₁₋₆ alkyl and R⁹ is C₁₋₆ alkyl which canoptionally contain one or more O, S or NR⁴ groups where R⁴ is hydrogenor C₁₋₆ alkyl.

The most preferred substituents for R and R¹ are those of the examplesexemplified herein.

Preferred compounds of the invention include:

-   4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile,-   4-Morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,-   4-(7-Azabicyclo[2.2.1]hept-7-yl)-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-piperidin-1-yl-1,3,5-triazine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-(ethylamino)-1,3,5-triazine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-(3-hydroxypyrrolidin-1-yl)-1,3,5-triazine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-[(2-piperidin-1-ylethyl)amino]-1,3,5-triazine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-(4-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile,-   4-[(3-Chlorobenzyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile,-   4-Morpholin-4-yl-6-[(4-morpholin-4-ylphenyl)amino]-1,3,5-triazine-2-carbonitrile,-   4-(2,3-Dihydro-1,4-benzodioxin-6-ylamino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,-   4-Morpholin-4-yl-6-(3-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile,-   4-(1,4′-Bipiperidin-1′-yl)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,-   4-[4-(1H-Imidazol-1-yl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,-   4-[4-(4-Chlorobenzoyl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,-   4-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-6-morpholinyl-1,3,5-triazine-2-carbonitrile,-   4-Morpholin-4-yl-6-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3,5-triazine-2-carbonitrile,-   1-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-diethylpiperidine-3-carboxamide,-   4-[4-(2-Methoxyphenyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,-   N˜2˜-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N˜1˜,N˜1˜-bis{4-[N-(4-cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N-isobutylglycyl]morpholin-3-yl}-N˜2˜-isobutylglycinamide,-   4-Morpholin-4-yl-6-[(2-pyridin-3-ylethyl)amino]-1,3,5-triazine-2-carbonitrile,-   4-{[2-(2-Furyl)ethyl]amino}-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,-   4[(4-Chlorophenyl)amino]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-carbonitrile,-   4-Azetidin-1-yl-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   4-[(4-Methylcyclohexyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   4-(4-Chlorophenoxy)-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-(dimethylamino)pyrimidine-2-carbonitrile,-   4-[(1-Methylpiperidin-4-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   4-(Cyclohexylamino)-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-ylpyrimidine-2-carbonitrile,-   4-[(6-Chloropyridin-3-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   1-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-prolinamide,-   4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]pyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-[(3-pyrrolidin-1-ylpropyl)amino]pyrimidine-2-carbonitrile,-   tert-Butyl    4-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}piperazine-1-carboxylate,-   4-[(4-Chlorophenyl)amino]-6-(cyclopropylamino)pyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-piperazin-1-ylpyrimidine-2-carbonitrile,-   (2S)-N˜2˜-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-N˜1˜,N˜1˜-bis[4-(N-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-leucyl)morpholin-3-yl]-L-leucinamide,-   5-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-5-methoxy-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   4-[(3S)-3-Aminopyrrolidin-1-yl]-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-5-methoxypyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-5-methoxypyrimidine-2-carbonitrile,-   4-[(4-Chlorophenyl)amino]-5-methoxy-6-(3-oxopiperazin-1-yl)pyrimidine-2-carbonitrile,-   1-{6-[(4-Chlorophenyl)amino]-2-cyano-5-methoxypyrimidin-4-yl}piperidine-3-carboxamide,-   4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile,-   5-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,-   5-Amino-4[(4-Chlorophenyl)amino]-6-(ethylamino)pyrimidine-2-carbonitrile,    and pharmaceutically acceptable salts thereof.

In a further aspect the invention provides a compound of formula (I) asdefined above but where X is CH, NHR², OR² where R² is preferably H orC₁₋₆ alkyl. For the novel compounds of the invention other preferredgroups and compounds are those defined above.

The present invention further provides a process for the preparation ofa compound of formula (I) which comprises

-   (i) reaction of a compound of general formula (II)

-    wherein L1, L2 and L3 represent a leaving group (e.g. halide,    sulphide, sulfoxide or sulphone group), preferably the sulphide is    oxidised to a sulphoxide or sulphone group before displacement. An    oxidising agent such as a peracid may be used, for example    meta-chloroperbenzoic acid in dichloromethane at room temperature.

L1 and L2 may be displaced by R and R¹ respectively where R and R¹ aredefined in formula (I) and L3 may be displaced by a cyanide salt. Thesequence of displacement of L1, L2 and L3 may be varied.

When X═CA and A=OR², SR² or CHR²R³ compounds of general formula (ID maybe formed by treatment of compounds of general formula (III) and (IV)with phosphorous oxychloride at reflux. R¹⁹ is preferably C₁₋₆ alkyl orbenzyl

-   (ii) when X═CA and A=NH₂ reaction of a compound of general    formula (V) under a hydrogen atmosphere with palladium catalyst at    room temperature.

According to a further feature of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable saltthereof, for use as a therapeutic agent.

According to a further feature of the present invention there isprovided a method for producing inhibition of a cysteine protease in awarm blooded animal, such as man, in need of such treatment, whichcomprises administering to said animal an effective amount of a compoundof the present invention, or a pharmaceutically acceptable salt thereof

The invention also provides a compound of the formula (I), or apharmaceutically acceptable salt thereof, for use as a medicament; andthe use of a compound of the formula (I) of the present invention, or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for use in the inhibition of a cysteine protease in a warmblooded animal, such as man. In particular the compounds of theinvention are useful in the treatment of inflammation and immunedisorders such as asthma, rheumatoid arthritis, COPD, multiplesclerosis, Crohn's disease, Alzheimers and pain, such as neuropathicpain. Preferably the compounds of the invention are used to treat pain,in particular neuropathic pain.

In particular the invention provides the use of a compound of theformula (I) of the present invention, or a pharmaceutically acceptablesalt thereof, in the manufacture of a medicament for use in theinhibition of Cathepsin S in a warm blooded animal, such as man. Inorder to use a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof for the therapeutic treatment of mammalsincluding humans, in particular in the inhibition of a cysteineprotease, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition.

Therefore in another aspect the present invention provides apharmaceutical composition which comprises a compound of the formula (I)or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable diluent or carrier.

The pharmaceutical compositions of this invention may be administered instandard manner for the disease condition that it is desired to treat,for example by oral, rectal or parenteral administration. For thesepurposes the compounds of this invention may be formulated by meansknown in the art into the form of, for example, tablets, capsules,aqueous or oily solutions or suspensions, (lipid) emulsions, dispersiblepowders, suppositories, ointments, creams, drops and sterile injectableaqueous or oily solutions or suspensions.

A suitable pharmaceutical composition of this invention is one suitablefor oral administration in unit dosage form, for example a tablet orcapsule which contains between 100 mg and 1 g of the compound of thisinvention.

In another aspect a pharmaceutical composition of the invention is onesuitable for intravenous, subcutaneous or intramuscular injection.

Each patient may receive, for example, an intravenous, subcutaneous orintramuscular dose of 1 mgkg⁻¹ to 100 mgkg⁻¹ of the compound, preferablyin the range of 5 mgkg⁻¹ to 20 mgkg⁻¹ of this invention, the compositionbeing administered 1 to 4 times per day. The intravenous, subcutaneousand intramuscular dose may be given by means of a bolus injection.Alternatively the intravenous dose may be given by continuous infusionover a period of time. Alternatively each patient will receive a dailyoral dose which is approximately equivalent to the daily parenteraldose, the composition being administered 1 to 4 times per day.

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula (I), or a pharmaceutically-acceptablesalt thereof (hereafter compound X), for therapeutic or prophylactic usein humans:

(a) Tablet I mg/tablet Compound X. 100 Lactose Ph.Eur. 179Croscarmellose sodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0(b) Tablet II mg/tablet Compound X 50 Lactose Ph.Eur. 229 Croscarmellosesodium 12.0 Polyvinylpyrrolidone 6 Magnesium stearate 3.0 (c) Tablet IIImg/tablet Compound X 1.0 Lactose Ph.Eur. 92 Croscarmellose sodium 4.0Polyvinylpyrrolidone 2.0 Magnesium stearate 1.0 (d) Capsule mg/capsuleCompound X 10 Lactose Ph.Eur. 389 Croscarmellose sodium 100 Magnesiumstearate 1. (e) Injection I (50 mg/ml) Compound X 5.0% w/v Isotonicaqueous solution to 100%

Buffers, pharmaceutically-acceptable cosolvents such as polyethyleneglycol, polypropylene glycol, glycerol or ethanol or complexing agentssuch as hydroxy-propyl β cyclodextrin may be used to aid formulation.

Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)–(c) may be entericcoated by conventional means, for example to provide a coating ofcellulose acetate phthalate.

The following examples illustrate the invention.

EXAMPLE 14-[(4-Chlorophenyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile

(i) 4,6-Dichloro-N-4-chlorophenyl)-1,3,5-triazin-2-amine

4-Chloroaniline (8.28 g) was added to a mixture of trichlorotriazine (6g) in acetone/ice-water (1:1, 60 ml) and stirred for 1 h. The solid wasfiltered off and dried to give a light brown solid, 8.5 g.

MS: APCI(+ve) 275/7(M+1)

(ii)6-Chloro-N˜2˜-(4-chlorophenyl)-N˜4˜,N˜4˜-dimethyl-1,3,5-triazine-2,4-diamine

A solution of dimethylamine in tetrahydrofuran (2M, 1.1 ml) was added toa mixture of the product from step (i) (0.3 g) in acetone (10 ml) andice-water (10 ml). After stirring for 1 h, the solid was filtered,washed with water and dried. Yield 0.3 g solid.

MS: APCI(+ve) 284(M+1)

(iii)4-[(4-Chlorophenyl)amino]-6-dimethylamino)-1,3,5-triazine-2-carbonitrile

Sodium cyanide (0.138 g) was added to a solution of the product fromstep (ii) (0.4 g) in N,N-dimethylformamide (20 ml) and heated at 90° C.for 16 h. The mixture was partitioned between ethyl acetate and water, asolid formed which was filtered off and purified by RPHPLC 15–85%acetonitrile in aqueous trifluoroacetic acid. Yield 0.05 g

MS: APCI(+ve) 275(M+1) 1H NMR: (DMSO-d6) δ 10.30(1H, bs), 7.72–7.37(4H,2×d), 3.14(6H, s)

EXAMPLE 24-Morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrile

(i) 2,4-Dichloro-6-morpholin-4-yl-1,3,5-triazine

Morpholine was added dropwise to stirred solution of trichlorotriazine(6.7 g), N,N-diisopropylethylamine (60.5 ml) in dichloromethane (50 ml)at −78° C. The solid formed was filtered off, washed with water, driedto give a white solid (6.7 g).

MS: APCI(+ve) 235(M+1)

(ii)4-Morpholin-4-yl-6-(4-phenoxypiperidin-1-yl)-1,3,5-triazine-2-carbonitrie

4-Phenoxypiperidine (0.15 g) was added to a solution of the product fromstep (i) (0.2 g), N,N-diisopropylethylamine (1.47 ml) in tetrahydrofuranand stirred at room temperature for 16 h. The solvent was evaporatedunder reduced pressure and the residue purified by chromatography onsilica eluting with ether/isohexane (1:2). Yield 0.3 g white solid. Thesolid was dissolved in N,N-dimethylformamide (20 ml), sodium cyanide(0.1 g) added and heated at 90° C. for 32 h. The mixture was partitionedbetween ethyl acetate and water, the organic layer separated, washedwith water, brine, dried (MgSO4) and evaporated under reduced pressure.The residue was purified by RPHPLC 35–95% acetonitrile in aqueoustrifluoroacetic acid. Yield 0.079 g

MS: APCI(+ve) 367(+H) 1H NMR: (DMSO-d6) δ 7.31–6.91(5H, m), 4.66(1H, m),4.11–4.04(2H, m), 3.70–3.57(10H, m), 2.00–1.95(2H, m), 1.63–1.60(2H, m)

EXAMPLES 3–26

Examples 3–26 were prepared according to the methods of example 1 or 2using the appropriate amines.

EXAMPLE 34-[(4-Chlorophenyl)amino]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 315(M−1) 1H NMR: (DMSO-d6) δ 10.41(1H, bs), 7.66–7.31(4H,2×d), 3.74–3.64(8H, m)

EXAMPLE 44-(7-Azabicyclo[2.2.1]hept-7-yl)-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 325(M−1) 1H NMR: (DMSO-d6) δ 10.37(1H, bs), 7.70–7.35(4H,2×d), 4.64–4.61(2H, m), 1.74–1.52(8H, m)

EXAMPLE 54-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 299(M−1) 1H NMR: (DMSO-d6) δ 10.29(1H, bs), 7.75–7.36(4H,2×d), 3.54–3.49(4H, m), 1.96–1.90(4H, m)

EXAMPLE 64-[(4-Chlorophenyl)amino]-6-piperidin-1-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 313(M−1) 1H NMR: (DMSO-d6) δ 10.29(1H, bs), 7.66–7.38(4H,2×d), 3.74–3.73(4H, m), 1.64–1.55(6H, m)

EXAMPLE 74-[(4-Chlorophenyl)amino]-6-(ethylamino)-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 273(M−1) 1H NMR: (DMSO-d6) δ 10.31(1H, bs), 8.39–7.34(5H,m), 3.36–3.27(2H, q), 1.10(3H, t)

EXAMPLE 84-[(4-Chlorophenyl)amino]-6-(3-hydroxypyrrolidin-1-yl)-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 315(M−1) 1H NMR: (DMSO-d6) δ 10.31(1H, s), 7.76–7.38 (4H,m), 5.06(1H, m), 4.38(1H, m), 366–3.45(4H, m), 2.04–1.95(2H, m)

EXAMPLE 94-[(4-Chlorophenyl)amino]-6-[(2-piperidin-1-ylethyl)amino]-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 358(M+1) 1H NMR: (DMSO-d6) δ 10.38(1H, s), 8.35–7.34(5H,m), 3.37(2H, m), 2.43–2.34(6H, m), 1.48–1.44(6H, m)

EXAMPLE 104-[(4-Chlorophenyl)amino]-6-(4-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 389(M−1) 1H NMR: (DMSO-d6) δ 10.33(1H, bs), 7.68–7.16(9H,m), 4.72–4.69(2H, d), 3.09–2.85(3H, m), 1.88–1.55(4H, m)

EXAMPLE 114-[(3-Chlorobenzyl)amino]-6-(dimethylamino)-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 287(M−1) 1H NMR: (DMSO-d6) δ 8.59–8.44(1H, t),7.37–7.22(4H, m), 4.47–4.44(2H, m), 3.07–3.03(6H, m)

EXAMPLE 124-Morpholin-4-yl-6-[(4-morpholin-4-ylphenyl)amino]-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 368(M+1) 1H NMR: (DMSO-d6) δ 10.09(1H, s), 7.57–7.48(2H,d), 6.93–6.84(2H, d), 3.72–3.55(12H, m), 3.07–3.00(4H, m)

EXAMPLE 134-(2,3-Dihydro-1,4-benzodioxin-6-ylamino)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 339(M−1) 1H NMR: (DMSO-d6) δ 10.13(1H, s), 7.21–6.80(3H,m), 4.23–3.64(12H, m)

EXAMPLE 144-Morpholin-4-yl-6-(3-phenylpiperidin-1-yl)-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 351(M+1) 1H NMR: (DMSO-d6) δ 7.35–7.22(5H, m),4.67–2.64(13H, m), 1.93–1.48(4H, m)

EXAMPLE 154-(1,4′-Bipiperidin-1′-yl)-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile,trifluoroacetate salt

MS: APCI(+ve) 358(M+1) 1H NMR: (DMSO-d6) δ 9.23(1H, bm), 4.75–4.64(2H,m), 3.71–3.36(11H, m), 2.93–2.87(4H, m), 2.08–1.37(10H, m)

EXAMPLE 164-[4-(1H-Imidazol-1-yl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 341(M+1) 1H NMR: (DMSO-d6) δ 9.11(11H, s), 7.89–7.88(1H,s), 7.69–7.68(1H, s), 4.79–4.62(3H, m), 3.74–3.02(10H, m), 2.17–1.88(4H,m)

EXAMPLE 174-[4-(4-Chlorobenzoyl)piperidin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 413(M+1) 1H NMR: (DMSO-d6) δ 8.04–8.02(2H, d),7.64–7.60(2H, d), 4.62–4.52(2H, m), 3.80–3.69(5H, m), 3.32–3.08(61H, m),1.87–1.43(4H, m)

EXAMPLE 184-[4-(5-Chloropyridin-2-yl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 387(M+1) 1H NMR: (DMSO-d6) δ 8.14–8.13(1H, s),7.65–7.62(1H, d), 6.91–6.89(1H, d), 3.82–3.57(16H, m)

EXAMPLE 194-Morpholin-4-yl-6-{[3-(2-oxopyrrolidin-1-yl)propyl]amino}-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 332(M+1) 1H NMR: (DMSO-d6) δ 8.10–8.07(1H, t),3.70–3.62(8H, m), 3.39–3.17(6H, m), 2.22–1.62(6H, m)

EXAMPLE 201-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N,N-diethylpiperidine-3-carboxamide

MS: APCI(+ve) 374(M+1) 1H NMR: (DMSO-d6) δ 4.39(2H, m), 3.78–3.60(4H,m), 3.33–2.63(11H, m), 1.80–1.43(4H, m), 1.16–0.92(6H, m)

EXAMPLE 214-[4-(2-Methoxyphenyl)piperazin-1-yl]-6-morpholin-4-yl-1,3,5-triazine-2-carbonitrile

MS: APCI(+ve) 382(M+1) 1H NMR: (DMSO-d6) δ 6.99–6.87(4H, m),3.86–3.63(15H, m), 2.99(4H, m)

EXAMPLE 22N˜2˜-(4-Cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N˜1˜,N˜1˜-bis{4-[N-4-cyano-6-morpholin-4-yl-1,3,5-triazin-2-yl)-N-isobutylglycyl]morpholin-3-yl}-N˜2˜-isobutylglycinamide

MS: APCI(+ve) 390(M+1) 1H NMR: (DMSO-d6) δ 4.39–4.36(2H, d),3.62–3.31(18H, m), 2.05–1.92(1H, m), 0.87–0.85(6H, d)

EXAMPLE 234-Morpholin-4-yl-6-[(2-pyridin-3-ylethyl)amino]-1,3,5-triazine-2-carbonitrile,trifluoroacetate salt

MS: APCI(+ve) 312(M+1) 1H NMR: (DMSO-d6) δ 8.69–8.64(2H, m),8.22–8.04(2H, m), 7.78–7.70(1H, m), 3.66–3.53(10H, m), 2.97–2.93(2H, t)

EXAMPLE 24 4-{[2-(2-Furyl)ethyl]amino}-6-morpholinyl-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 299(M+1) 1H NMR: (DMSO-d6) δ 8.21(1H, t), 7.51(1H, s),6.34(1H, s), 6.15(1H, s), 3.64–3.62(8H, m), 3.52–3.46(2H, m),2.86–2.82(2H, m)

EXAMPLE 254-[(4-Chlorophenyl)amino]-6-(4-methylpiperazin-1-yl)-1,3,5-triazine-2-carbonitrile,trifluoroacetate salt

MS: APCI(+ve) 330(M+1) 1H NMR: (DMSO-d6) δ 10.56(1H, bs), 10.05(1H,brs), 7.66–7.40(4H, m), 3.41–3.35(8H, m), 2.81(3H, s)

EXAMPLE 264-Azetidin-1-yl-6-[(4-chlorophenyl)amino]-1,3,5-triazine-2-carbonitrile

MS: APCI(−ve) 285(M−1) 1H NMR: (DMSO-d6) δ 10.32(1H, s), 7.72–7.32(4H,m), 4.15–4.10(4H, m), 2.38–2.30(2H, q)

EXAMPLE 274-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

(i) N-(4-Chlorophenyl)-2,6-difluoropyrimidin-4-amine

4-Chloroaniline was added to a stirred solution of2,4,6-trifluoropyrimidine (7.7 g), potassium carbonate (7.86 g) inethanol (80 ml). The mixture was stirred at room temperature for 16 h,diluted with water, extracted with ethyl acetate, dried (MgSO4) andevaporated under reduced pressure. The residue was purified bychromatography on silica eluting with isohexane/ethyl acetate (4:1).Yield 8.3 g cream solid

1H NMR: (DMSO-d6) δ 10.47(1H, s), 7.58(211, d), 7.45(2H, d), 6.35(1H, s)

(ii) 4-[(4-Chlorophenyl)amino]-6-fluoropyrimidine-2-carbonitrile

Sodium cyanide (0.046 g) was added to a solution of the product fromstep (i) (0.113 g) in dimethylsulphoxide (3 ml) and stirred at roomtemperature for 1.5 h. The mixture was partitioned between ethyl acetateand water, the organics washed with water, dried (MgSO4), and evaporatedunder reduced pressure. The residue was purified by chromatography onsilica eluting with isohexane/ethyl acetate (4:1). Yield 0.036 g

1H NMR: (DMSO-d6) δ 10.56(1H, s), 7.57(2H, d), 7.47(2H, d), 6.65(1H, s)

(iii)4-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

Morpholine (0.16 g) was added to a solution of the product from step(ii) (0.16 g) in iso-propylalcohol (4 ml) and stirred for 2 h at roomtemperature. The mixture was partitioned between ethyl acetate andaqueous sodium hydrogencarbonate solution, the organics separated, dried(MgSO4) and evaporated under reduced pressure. The residue was purifiedby chromatography on silica eluting with isohexane/ethyl acetate (1:1).Yield 0.09 g

MS: APCI(+ve) 316(M+1) 1H NMR: (DMSO-d6) δ 9.65(1H, s), 7.52(2H, d),7.38(2H, d), 6.08(1H, s), 3.67(4H, t), 3.48(2H, t)

EXAMPLES 28–42

Examples 28–42 were prepared according to the general method of example27 using the appropriate amines or phenols

EXAMPLE 284-[(4-Methylcyclohexyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 302(M+1) 1H NMR: (DMSO-d6) δ 7.21–7.18(1H, d), 5.83(H, s),3.89(1H, bs), 3.88(4H, m), 3.41(4H, m), 1.63–1.28(9H, m), 0.89(3H, d)

EXAMPLE 29 4-(4-Chlorophenoxy)-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(−ve) 315(M−1) 1H NMR: (DMSO-d6) δ 7.53–7.20(4H, 2×d), 6.63(1H,s), 3.65–3.63(8H, m)

EXAMPLE 304-[(4-Chlorophenyl)amino]-6-(dimethylamino)pyrimidine-2-carbonitrile

MS: APCI(+ve) 274(M+1) 1H NMR: (DMSO-d6) δ 9.57(1H, s), 7.55–7.34(4H,2×d), 5.93(1H, s), 3.02(6H, m)

EXAMPLE 31 4[(1-Methylpiperidin4-yl)amino]-morpholin-4-ylpyrimidine-2-carbonitrile, trifluoroacetatesalt

MS: APCI(+ve) 303(M+1) 1H NMR: (DMSO-d6) δ 9.36(1H, brs), 7.49–7.47(1H,d), 5.76(1H, s), 3.92(1H, bm), 3.67–3.43(8H, 2×m), 3.34–3.10(4H, m),2.75(3H, s), 2.07–1.68(4H, m)

EXAMPLE 32 4-(Cyclohexylamino)-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 288(M+1) 1H NMR: (DMSO-d6) δ 7.23–7.21(1H, d), 5.73(1H,s), 3.62–3.42(9H, m), 1.83–1.07(10H, m)

EXAMPLE 334[(4-Chlorophenyl)amino]-6-pyrrolidin-1-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 300(M+1) 1H NMR: (DMSO-d6) δ 9.55(1H, s), 7.54–7.35(4H,2×d), 5.79(1H, s), 3.38(4H, m), 1.93(4H, m)

EXAMPLE 344-[(6-Chloropyridin-3-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(−ve) 315(M−1) 1H NMR: (DMSO-d6) δ 9.83(1H, s), 8.55–8.49(1H,s), 8.06–8.02(1H, d), 7.49–7.46(1H, d), 6.10(1H, s), 3.69–3.66(4H, m),3.52–3.48(4H, m)

EXAMPLE 351-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-prolinamide

MS: APCI(+ve) 343(M+1) 1H NMR: (DMSO-d6) δ 9.33(1H, s), 7.57–7.24(4H,2×d), 7.00(2H, bm), 5.81(1H, s), 4.31–3.38(3H, m), 2.26–1.26(4H, m)

EXAMPLE 364-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]pyrimidine-2-carbonitrile,trifluoroacetate salt

MS: APCI(+ve) 329(M+1) 1H NMR: (DMSO-d6) δ 9.66(1H, s), 7.88–7.36(7H,m), 6.15(1H, s), 4.23–4.20(2H, m), 3.17–2.96(3H, m), 1.98–1.38(4H, m)

EXAMPLE 374-[(4-Chlorophenyl)amino]-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidine-2-carbonitrile,acetate salt

MS: APCI(+ve) 383(M+1) 1H NMR: (DMSO-d6) δ 9.57(1H, s), 7.53–7.35(4H,2×d), 6.09(1H, s), 4.06–2.51(9H, m), 1.92–1.90(5H, m), 1.74–1.34(6H, m)

EXAMPLE 384-[(4-Chlorophenyl)amino]-6-[(3-pyrrolidin-1-ylpropyl)amino]pyrimidine-2-carbonitrile,trifluoroacetate salt

MS: APCI(+ve) 357(M+1) 1H NMR: (DMSO-d6) δ 9.52(2H, m), 7.63–7.36(5H,2×d+m), 5.92(1H, bs), 3.54–2.99(8H, m), 2.00–1.84(6H, m)

EXAMPLE 39 tert-Butyl4-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}piperazine-1-carboxylate

MS: APCI(+ve) 415(M+1) 1H NMR: (DMSO-d6) δ 9.66(1H, s), 7.52(2H—, d),7.37(2H, d), 6.07(11H, s), 3.54–3.51(4H, m), 3.44–3.41(4H, m), 1.42(9H,s)

EXAMPLE 404-[(4-Chlorophenyl)amino]-6-(cyclopropylamino)pyrimidine-2-carbonitrile

MS: APCI(+ve) 286(M+1) 1H NMR: (DMSO-d6) δ 9.65(1H, s), 7.80(1H, s),7.53(2H, d), 7.37(2H, d), 6.08(1H, s), 0.76–0.71(2H, m), 0.50–0.46(2H,m)

EXAMPLE 414-[(4-Chlorophenyl)amino]-6-piperazin-1-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 315(M+1) 1H NMR: (DMSO-d6) δ 9.62(1H, s), 7.53(2H, d),7.37(2H, d), 6.07(1H, s), 3.46(4H, t), 2.79(4H, t)

EXAMPLE 42(2S)-N˜2˜-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-N˜1˜,N˜1˜-bis[4-(N-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-leucyl)morpholin-3-yl]-L-leucinamide

MS: APCI(+ve) 429(M+1) 1H NMR: (DMSO-d6) δ 9.51(1H, s), 7.82(1H, d),7.46(2H, d), 7.37(2H, d), 6.09(1H, s), 4.87(1H, s), 3.67–3.47(6H, m),3.35–3.25(2H, m), 1.66–1.53(2H, m), 1.48–1.39(1H, m), 0.92–0.89(6H, m)

EXAMPLE 435-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

(i) 4-(5-Chloro-2,6-difluoropyrimidin-4-yl)morpholine

Morpholine (0.774 mg) was added to a solution of5-chloro-2,4,6-trifluoropyrimidine (1.5 g), N,N-diisopropylethylamine(1.15 g) in 1,4-dioxane (30 ml) and stirred at room temperature for 16h. The mixture was partitioned between ethyl acetate and water, theorganic layer dried (MgSO4) and evaporated under reduced pressure. Theresidue was purified by chromatography on silica eluting with 8% ethylacetate in isohexane. Yield 0.88 g

(ii)5-Chloro-N-(4-chlorophenyl)-2-fluoro-6-morpholin-4-ylpyrimidin-4-amine

4-Chloroaniline (1.44 g) was added to a solution of the product fromstep (i) (0.88 g) and N,N-diisopropylethylamine (0.484 g) in 1,4-dioxane(15 ml) and isopropylalcohol (15 ml) and the mixture heated at 110° C.for 6 days. The mixture was partitioned between ethyl acetate and water,the organics dried (MgSO4), and evaporated under reduced pressure. Thesolid was triturated with ethyl acetate, filtered and the filtratepurified by chromatography on silica eluting with 3% ethyl acetate intoluene. Yield 0.28 g

MS: APCI(+ve) 343/5(M+1)

(iii)5-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

Sodium cyanide (0.057 g) was added to a solution of the product fromstep (ii) (0.2 g) in dimethylsulphoxide (5 ml) and the mixture stirredat room temperature. After 18 h, the mixture was partitioned betweenethyl acetate and water, the organics separated, washed with water,dried (MgSO4) and evaporated under reduced pressure. The residue waspurified by chromatography on silica eluting with 5% ethyl acetate intoluene. Yield 0.09 g

MS: APCI(−ve) 348(M−1) 1H NMR: (DMSO-d6) δ 9.34(1H, s), 7.53(2H, d),7.42(2H, d), 3.71(4H, t), 3.55(4H, t)

EXAMPLE 444-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile,trifluoroacetate salt

(i) 5-Methoxy-2-thioxodihydropyrimidine-4,6(1H,5H)-dione

Thiourea (24 g) and methoxymethyl malonate (34 g) was added to asolution of sodium (12 g) in methanol and the mixture heated underreflux for 10 h. The methanol was evaporated under reduced pressure,water (500 ml) added and extracted with ether. The aqueous layer wasacidified to pH1 with conc. hydrochloric acid, evaporated to ˜200 ml andthe precipitate filtered and dried. Yield 23 g

1H NMR: (DMSO-d6) δ 11.31(2H, s), 3.48(3H, s)

(ii) 2-(Ethylthio)-5-methoxypyrimidine-4,6(1H,5H)-dione

Ethyl iodide (11.2 ml) was added dropwise to a stirred mixture of theproduct from step (i) (23 g) and sodium hydroxide (6 g) in water (400ml). After 16 h the mixture was filtered, the filtrate acidified to pH1and the precipitate filtered, washed with water and dried. Yield 17.8 g

1H NMR: (DMSO-d6) δ 12.25(1H, s), 3.59(3H, s), 3.57(1H, s), 3.06(2H, q),1.28(3H, t)

(iii) 4,6-Dichloro-2-(ethylthio)-5-methoxypyrimidine

A mixture of the product from step (ii) (17.8 g) and N,N-diethylaniline(20 ml) in phosphorus oxychloride (400 ml) was heated at 100° C. for 3h. The excess reagent was removed under reduced pressure and the residuepoured onto ice and extracted with ether. The ether layer was washedwith water, dried (MgSO4) and evaporated under reduced pressure. Theresidue was purified by chromatography on silica eluting with 5% ethylacetate in isohexane. Yield 12.8 g

(iv)6-Chloro-N-(4-chlorophenyl)-2-(ethylthio)-5-methoxypyrimidin-4-amine

A solution of the product from step (iii) (4 g) and 4-chloroaniline (5.3g) in ethanol (40 ml) was heated under reflux for 16 h then the solventremoved under reduced pressure. The residue was partitioned betweenethyl acetate and 2M hydrochloric acid, the organics washed with water,dried (MgSO4) and evaporated under reduced pressure. The residue waspurified by chromatography on silica eluting with 10–15% ethyl acetatein isohexane. Yield 4.99 g

MS: APCI(+ve) 330/2(M+1)

(v)4-Chloro-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile

A mixture of the product from step (iv) (4.9 g) and3-chloroperoxybenzoic acid (10 g, Aldrich 77% max.) in dichloromethane(150 ml) was stirred at room temperature for 3 h, washed with aqueoussodium metabisulphite solution, water, aqueous sodium hydrogencarbonatesolution, water, dried (MgSO4) and evaporated under reduced pressure.The solid was dissolved in dimethylsulphoxide (40 ml), sodium cyanide(1.1 g) added and stirred for 2 h at room temperature. The mixture waspartitioned between ethyl acetate and water, the organics dried (MgSO4)and evaporated under reduced pressure. The residue was purified bychromatography on silica eluting with 30% ethyl acetate in isohexane.Yield 3.23 g

MS: APCI(+ve) 295/7(M+1)

(vi)4-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile

A solution of the product from step (v) (0.25 g) and piperazine (0.366g) in tetrahydrofuran (8 ml) was heated at 60° C. for 6 h then thesolvent removed under reduced pressure. The residue was purified byRPHPLC 15–75% acetonitrile in aqueous trifluoroacetic acid. Yield 0.139g

MS: APCI(+ve) 345(M+1) 1H NMR: (DMSO-d6) δ 9.29(1H, s), 8.92(2H, s),7.67(2H, d), 7.40(2H, d), 3.83–3.80(4H, m), 3.69(3H, s), 3.25–3.23(4H,m) Mpt 230° C.

EXAMPLES 45–51

Examples 45–51 were prepared according to the method of example 44 usingthe appropriate amines

EXAMPLE 454-[(4-Chlorophenyl)amino]-5-methoxy-6-morpholin-4-ylpyrimidine-2-carbonitrile

MS: APCI(+ve) 346(M+1) 1H NMR: (DMSO-d6) δ 9.20(1H, s), 7.67(2H, d),7.38(2H, d), 3.73–3.70(4H, m), 3.68(3H, s), 3.63–3.61(4H, m) Mpt 176° C.

EXAMPLE 464-[(3S)-3-Aminopyrrolidin-1-yl]-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile,trifluoroacetate salt

MS: APCI(+ve) 345/7(M+1) 1H NMR: (DMSO-d6) δ 9.12(1H, s), 8.10(3H, s),7.66(2H, d), 7.38(2H, d), 3.91–3.69(5H, m), 3.65(3H, s), 2.33–2.22(1H,m), 2.08–2.01(1H, m) Mpt 345–7° C.

EXAMPLE 474-[(4-Chlorophenyl)amino]-6-{4-[3-(dimethylamino)propyl]piperazin-1-yl}-5-methoxypyrimidine-2-carbonitrile,bis-trifluoroacetate salt

MS: APCI(+ve) 430/2(M+1) 1H NMR: (DMSO-d6) 90° C. δ 8.94(11, s),7.64(2H, d), 7.35(2H, d), 3.81(4H, brs), 3.70(3H, s), 3.15–3.09(2H, m),3.00(4H, brs), 2.86(2H, brs), 2.81(6H, s), 2.03–1.95(2H, m) Mpt 210–2°C.

EXAMPLE 484-[(4-Chlorophenyl)amino]-6-(dimethylamino)₅-methoxypyrimidine-2-carbonitrile

MS: APCI(−ve) 302/4(M−1) 1H NMR: (DMSO-d6) 90° C. δ 9.08(1H, s),7.66(2H, d), 7.37(2H, d), 3.62(3H, s), 3.13(6H, s) Mpt 173° C.

EXAMPLE 494-[(4-Chlorophenyl)amino]-5-methoxy-6(3-oxopiperazin-1-yl)pyrimidine-2-carbonitrile

MS: APCI(−ve) 357/9(M−1) 1H NMR: (DMSO-d6) δ 9.24(1H, s), 8.10(1H, s),7.67(2H, d), 7.39(2H, d), 4.17(2H, s), 3.85–3.83(2H, m), 3.66(3H, s),3.32–3.29(2H, m) Mpt 244° C.

EXAMPLE 501-{6-[(4-Chlorophenyl)amino]-2-cyano-5-methoxypyrimidin-4-yl}piperidine-3-carboxamide

MS: APCI(+ve) 387/9 (M+1) 1H NMR: (DMSO-d6) δ 9.16(1H, s), 7.68(2H, d),7.40–7.35(3H, m), 6.89(1H, s), 4.34–4.25(2H, m), 3.65(3H, s),3.07–2.92(2H, m), 2.35–2.40(1H, m), 1.90–1.51(4H, m)

EXAMPLE 514-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile,trifluoroacetate salt

MS: APCI(+ve) 359/61 (M+1) 1H NMR: (DMSO-d6) δ 9.20(1H, s), 7.93(3H, s),7.67(2H, d), 7.39(2H, d), 4.36–4.32(2H, m), 3.66(3H, s), 3.08–3.01(2H,m), 2.00–1.97(2H, m), 1.57–1.54(2H, m)

EXAMPLE 525-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

(i)N-(4-Chlorophenyl)-6-morpholin-4-yl-5-nitro-2-(propylthio)pyrimidin-4-amine

Morpholine (1.31 ml) was added dropwise to a stirred solution of4,6-dichloro-5-nitro-2-thiopropyl pyrimidine (4 g), N,N-diisopropylamine(7 ml) in dichloromethane (50 ml) at 0° C. After 1 h, 4-chloroaniline(1.9 g) was added, the mixture stirred at room temperature for 24 h,then heated under reflux for 24 h. The mixture was partitioned betweendichloromethane and 2M hydrochloric acid, the organics washed withwater, dried (MgSO4) and evaporated under reduced pressure. Yield 5 g

MS: APCI(+ve) 410/2 (M+1)

(ii)4-[(4-Chlorophenyl)amino]-6-morpholin-4-yl-5-nitropyrimidine-2-carbonitrile

A mixture of the product from step (i) (5 g) and 3-chloroperoxybenzoicacid (12 g, Aldrich 77% max.) in dichloromethane (200 ml) was stirred atroom temperature for 2 h, washed with aqueous sodium metabisulphitesolution, water, aqueous sodium hydrogencarbonate solution, water, dried(MgSO4) and evaporated under reduced pressure. The solid was dissolvedin dimethylsulphoxide (30 ml), sodium cyanide (2 g) added and stirredfor 1 h at room temperature. Water (500 ml) was added and the solidfiltered, washed with water, dried and the residue triturated withether. Yield 1.7 g

MS: APCI(+ve) 361/3 (M+1)

(iii)5-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile

The product from step (ii) (1.7 g) and 10% palladium on charcoal (0.2 g)in ethyl acetate (300 ml) was hydrogenated at 2 Bar for 8 h, filteredthrough celite and the solvent evaporated under reduced pressure. Yield1.05 g

MS: APCI(+ve) 329/331 (M+1) 1H NMR: (DMSO-d6) δ 8.66(1H, s), 7.62(2H,d), 7.39(2H, d), 5.53(2H, s), 3.78–3.76(4H, m), 3.08–3.06(4H, m) Mpt253–4° C.

EXAMPLE 535-Amino-4[(4-Chlorophenyl)amino]-6(ethylamino)pyrimidine-2-carbonitrile

Example 53 was prepared according to the general method of example 52using the appropriate amine

MS: APCI(+ve) 289/91(M+1) 1H NMR: (DMSO-d6) δ 8.19(1H, s), 7.50(2H, d),7.31(2H, d), 6.52(1H, t), 5.20(2H, s), 3.41–3.35(2H, m), 1.18(3H, t) Mpt211–2° C.

Measurement of Cathepsin S Activity.

QFRET Technology (Quenched Fluorescent Resonance Energy Transfer) wasused to measure the inhibition by test compounds of Cathepsin S-mediatedcleavage of the synthetic peptide Z-Val-Val-Arg-AMC. Compounds werescreened at five concentrations in duplicate and the pIC₅₀ valuesreported.

Synthetic substrate, 20 μM [final]Z-Val-Val-Arg-AMC in phosphate bufferwere added to a 96 well black Optiplate. The assay plates were pre-readfor compound auto fluorescence on SpectraMax Gemini at 355 nM excitationand 460 nM emission. 250 pM [final] rHuman Cathepsin S in phosphatebuffer was added and incubated for 2 h at room temperature on theSpectraMax Gemini, taking readings every 20 min at 355 nM excitation and460 nM emission.

Activity Based template (5PTB-8) used the auto fluorescent correcteddata to calculate the percentage inhibition for each compoundconcentration using the relevent plate controls. This data was used toconstruct inhibition curves and pIC₅₀ estimated by non-linear regressionusing a 4 parameter logistic model.

1. A pharmaceutical composition which comprises a compound of formula(I):

in which: X is CA where A is hydrogen, halogen, CHR²R³, OR², NR²R³, orSR²; R² and R³ are independently hydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkylboth of which can optionally contain one or more O, S or NR⁴ groupswhere R⁴ is hydrogen or C₁₋₆ alkyl, and can be optionally substituted byaryl, heteroaryl, NR⁵R⁶ where R⁵ and R⁶ together with the nitrogen atomto which they are attached form a 4–7 membered ring optionallycontaining a further O, S, NR⁴, or R2 and R3 together with the nitrogenatom to which they are attached form a 4–7 membered ring optionallycontaining a further O, S, NR⁴ group, or R2 and R3 are aryl orheteroaryl groups, both aryl and heteroaryl groups being optionallysubstituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR⁷R⁸,SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy,methylenedioxy, C₁₋₆alkyl, C₁₋₆alkoxy, NR⁷R⁸ or SR⁷ where R⁷ and R⁸ areindependently hydrogen or C₁₋₆ alkyl; R and R¹ are independently a groupY(CH₂)pR⁹ where p is 0, 1, 2 or 3 and Y is O or NR¹⁰ where R¹⁰ ishydrogen, C₁₋₆ alkyl or C₃₋₆ cycloalkyl; and R⁹ is hydrogen, C₁₋₆ alkylwhich can optionally contain one or more O, S or NR⁴ groups where R⁴ ishydrogen or C₁₋₆ alkyl, or a 3 to 7-membered saturated ring optionallycontaining a carbonyl group, one or more O, S or N atoms, or an aryl orheteroaryl group containing one to four heteroatoms selected from O, Sor N, the saturated ring, aryl and heteroaryl groups all beingoptionally substituted by halogen, amino, hydroxy, cyano, nitro,carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴,ethylenedioxy, methylenedioxy, C₁₋₆ alkyl, C₁₋₆alkoxy, SR⁵ or NR¹¹R¹²where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or togetherwith the nitrogen atom to which they are attached form a 5- or6-membered saturated ring optionally containing a further O, S or NR⁴group; or R/R¹ is a group NR¹⁰(CHR¹⁰) CONR²R³ or NR¹⁰(CH₂)_(q)CONR²R³where q is 1, 2 or 3; or R/R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴together with the nitrogen atom to which they are attached form a 4 to7-membered saturated ring optionally containing a carbonyl group, O, Sor N atom and optionally substituted by C₁₋₆alkyl, amino, hydroxy,CO₂C₁₋₆alkyl, halogen, NR⁵R⁶, NR⁷R⁸, C₁₋₆ alkylNR¹⁷R¹⁸ where R¹⁷ and R¹⁸are independently hydrogen or C₁₋₆ alkyl, CONR¹⁵R¹⁶ where R¹⁵ and R¹⁶are independently hydrogen or C₁₋₆ alkyl, or optionally substituted byaryl, phenoxy, COphenyl, or a heteroaryl group, the latter four groupsbeing optionally substituted by halogen, amino, hydroxy, cyano, nitro,carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴,ethylenedioxy, methylenedioxy, C₁₋₆alkyl, C₁₋₆alkoxy, SR⁵ or NR¹¹R¹²where R¹¹ and R¹² are independently hydrogen, C₁₋₆ alkyl or togetherwith the nitrogen atom to which they are attached form a 5- or6-membered saturated ring optionally containing a further O, S or NR⁴group; or a pharmaceutically acceptable salt thereof; and apharmaceutically acceptable diluent or carrier.
 2. A method treatingrheumatoid arthritis in a mammal comprising administering an effectiveamount of a compound of formula (I) to said mammal

in which: X is CA where A is hydrogen, halogen, CHR²R³, OR², NR²R³, orSR²; R² and R³ are independently hydrogen, C₁₋₆alkyl or C₃₋₆ cycloalkylboth of which can optionally contain one or more O, S or NR⁴ groupswhere R⁴ is hydrogen or C₁₋₆alkyl, and can be optionally substituted byaryl, heteroaryl, NR⁵R⁶ where R⁵ and R⁶ together with the nitrogen atomto which they are attached form a 4–7 membered ring optionallycontaining a further O, S, NR⁴, or R2 and R3 together with the nitrogenatom to which they are attached form a 4–7 membered ring optionallycontaining a further O, S, NR⁴ group, or R2 and R3 are aryl orheteroaryl groups, both aryl and heteroaryl groups being optionallysubstituted by halogen, amino, hydroxy, cyano, nitro, carboxy, CONR⁷R⁸,SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴, ethylenedioxy,methylenedioxy, C₁₋₆alkyl, C₁₋₆alkoxy, NR⁷R⁸ or SR⁷ where R⁷ and R⁸ areindependently hydrogen or C₁₋₆alkyl; R and R¹ are independently a groupY(CH₂)pR⁹ where p is 0, 1, 2 or 3 and Y is O or NR¹⁰ where R¹⁰ ishydrogen, C₁₋₆alkyl or C₃₋₆cycloalkyl; and R⁹ is hydrogen, C₁₋₆alkylwhich can optionally contain one or more O, S or NR⁴ groups where R⁴ ishydrogen or C₁₋₆ alkyl, or a 3 to 7-membered saturated ring optionallycontaining a carbonyl group, one or more O, S or N atoms, or an aryl orheteroaryl group containing one to four heteroatoms selected from O, Sor N, the saturated ring, aryl and heteroaryl groups all beingoptionally substituted by halogen, amino, hydroxy, cyano, nitro,carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴,ethylenedioxy, methylenedioxy, C₁₋₆alkyl, C₁₋₆alkoxy, SR⁵ or NR¹¹R¹²where R¹¹ and R¹² are independently hydrogen, C₁₋₆alkyl or together withthe nitrogen atom to which they are attached form a 5- or 6-memberedsaturated ring optionally containing a further O, S or NR⁴ group; orR/R¹ is a group NR¹⁰(CHR¹⁰) CONR²R³ or NR¹⁰(CH₂)_(q)CONR²R³ where q is1, 2 or 3; or R/R¹ is a group NR¹³R¹⁴ where R¹³ and R¹⁴ together withthe nitrogen atom to which they are attached form a 4 to 7-memberedsaturated ring optionally containing a carbonyl group, O, S or N atomand optionally substituted by C₁₋₆ alkyl, amino, hydroxy, CO₂C₁₋₆alkyl,halogen, NR⁵R⁶, NR⁷R^(8, C) ₁₋₆ alkylNR¹⁷R¹⁸ where R¹⁷ and R¹⁸ areindependently hydrogen or C₁₋₆ alkyl, CONR¹⁵R¹⁶ where R¹⁵ and R¹⁶ areindependently hydrogen or C₁₋₆ alkyl, or optionally substituted by aryl,phenoxy, COphenyl, or a heteroaryl group, the latter four groups beingoptionally substituted by halogen, amino, hydroxy, cyano, nitro,carboxy, CONR⁷R⁸, SO₂NR⁷R⁸, SO₂R⁴, trifluoromethyl, NHSO₂R⁴, NHCOR⁴,ethylenedioxy, methylenedioxy, C₁₋₆alkyl, C₁₋₆alkoxy, SR⁵ or NR¹¹R¹²where R¹¹ and R¹² are independently hydrogen, C₁₋₆alkyl or together withthe nitrogen atom to which they are attached form a 5- or 6-memberedsaturated ring optionally containing a further O, S or NR⁴ group; or apharmaceutically acceptable salt.
 3. The method according to claim 2 inwhich A is H, NHR², or OR² wherein R² is hydrogen or C₁₋₆alkyl.
 4. Themethod according to claim 2 in which R is a group Y(CH₂)pR⁷ where p is 0or 1 and Y is NR⁸ wherein R⁸ is hydrogen and R⁷ is substituted phenyl.5. The method according to claim 2 in which R¹ is a group NR¹³R¹⁴ whereR¹³ and R¹⁴ together with the nitrogen atom to which they are attachedform a morpholine ring, piperidine or piperazine ring optionallysubstituted.
 6. The method according to claim 2 in which R¹ is a groupNR⁹R¹⁰ where R¹⁰ is H or C₁₋₆alkyl and R⁹ is C₁₋₆alkyl which canoptionally contain one or more O, S or NR⁴ groups where R⁴ is hydrogenor C₁₋₆alkyl.
 7. The method according to claim 2 where the compound offormula (I) is selected from:4-[(4-Chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,4-[(4-Methylcyclohexyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,4-(4-Chlorophenoxy)-6-morpholin-4-ylpyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-6-(dimethylamino)pyrimidine-2-carbonitrile,4-[(1-Methylpiperidin-4-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,4-(Cyclohexylamino)-6-morpholin-4-ylpyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-6-pyrrolidin-1-ylpyrimidine-2-carbonitrile,4-[(6-Chloropyridin-3-yl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,1 -{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-prolinamide,4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]pyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-6-(4-pyrrolidin-1-ylpiperidin-1-yl)pyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-6-[(3-pyrrolidin-1-ylpropyl)amino]pyrimidine-2-carbonitrile, tert-Butyl4-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}piperazine-1-carboxylate,4-[(4-Chlorophenyl)amino]-6-(cyclopropylamino)pyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-6-piperazin-1-ylpyrimidine-2-carbonitrile,(2S)-N˜2˜-{6-[(4-Chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-N˜1˜,N˜1˜-bis[4-(N-{6-[(4-chlorophenyl)amino]-2-cyanopyrimidin-4-yl}-L-leucyl)morpholin-3-yl]-L-leucinamide,5-Chloro-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-5-methoxy-6-piperazin-1-ylpyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-5-methoxy-6-morpholin-4-ylpyrimidine-2-carbonitrile,4-[(3S)-3-Aminopyrrolidin-1-yl]-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-6-{4-[3-(dimethylamino) propyl]piperazin-1-yl}-5-methoxypyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-6-(dimethylamino)-5-methoxypyrimidine-2-carbonitrile,4-[(4-Chlorophenyl)amino]-5-methoxy-6-(3-oxopiperazin-1-yl)pyrimidine-2-carbonitrile,1-{6-[(4-Chlorophenyl)amino]-2-cyano-5-methoxypyrimidin-4-yl}piperidine-3-carboxamide,4-(4-Aminopiperidin-1-yl)-6-[(4-chlorophenyl)amino]-5-methoxypyrimidine-2-carbonitrile,5-Amino-4-[(4-chlorophenyl)amino]-6-morpholin-4-ylpyrimidine-2-carbonitrile,and5-Amino-4-[(4-Chlorophenyl)amino]-6-(ethylamino)pyrimidine-2-carbonitrile.